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Efficacy and Safety of Abiraterone Acetate in an Elderly Patient Subgroup (Aged 75 and Older) with Metastatic Castration-resistant Prostate Cancer After Docetaxel-based Chemotherapy

European Urology, 5, 65, pages 875 - 883

Abstract

Background

Metastatic castration-resistant prostate cancer (mCRPC) is a disease that primarily affects older men. Abiraterone acetate (AA), a selective androgen biosynthesis inhibitor, in combination with low-dose prednisone (P) improved overall survival (OS) in a randomised trial in mCRPC progressing after docetaxel versus placebo (PL) plus P.

Objective

To examine the efficacy and safety of AA plus P versus PL plus P in subgroups of elderly (aged ≥75 yr) (n = 331) and younger patients (<75 yr) (n = 863).

Design, setting, and participants

We conducted a post hoc analysis of a randomised double-blind PL-controlled study in mCRPC patients progressing after docetaxel chemotherapy.

Intervention

Patients were randomised 2:1 to AA (1000 mg) plus low-dose P (5 mg twice daily) (n = 797) or PL plus P (n = 398).

Outcome measurements and statistical analysis

Primary end point was OS. Secondary end points were time to prostate-specific antigen (PSA) progression (TTPP), radiographic progression-free survival (rPFS), and PSA response rate. Treatment differences were compared using the stratified log-rank test. The Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). The key limitation was the post hoc analysis.

Results and limitations

Elderly patients treated with AA plus P showed improved OS (HR: 0.64; 95% CI, 0.478–0.853; p = 0.0022), TTPP (HR: 0.76; 95% CI, 0.503–1.155; p = 0.1995), and rPFS (HR: 0.66; 95% CI, 0.506–0.859; p = 0.0019), and higher PSA response rate with relative risk (HR: 4.15; 95% CI, 2.2–8.0]; p ≤ 0.0001) compared with patients treated with PL plus P. Grade 3/4 adverse events occurred in 62% of elderly patients and in 60% of patients aged <75 yr treated with AA plus P. Incidences of hypertension and hypokalaemia, although increased in the AA plus P arm, were similar in both age subgroups and readily managed.

Conclusions

AA improves OS and is well tolerated in both elderly patients and younger patients with mCRPC following docetaxel, hence providing an important treatment option for elderly patients who may not tolerate alternative therapies with greater toxicity.

Trial registration

ClinicalTrials.gov, identifier NCT00638690 .

Take Home Message

This post hoc analysis of study COU-AA-301 confirms the clinical benefit of abiraterone acetate (AA) and prednisone, achieved by targeting persistent androgen synthesis and androgen signalling, in elderly patients with metastatic castration-resistant prostate cancer in a postdocetaxel patient population. AA is an important treatment option for elderly patients who might not be able to tolerate alternative cytotoxic therapies with greater toxicities.

Keywords: Abiraterone acetate, Elderly, Metastatic castration-resistant prostate cancer.

1. Introduction

Relative to the 2011 world population, recent United Nations projections estimate that by 2100 the number of people aged >60 yr will triple, with a greater increase in the age group >80 yr (eightfold) [1] . An analysis of the US Surveillance Epidemiology and End Results database indicates that elderly patients aged ≥75 yr have a greater risk for prostate cancer (PCa)-related death than for death of any other cancer cause and account for more than half of the deaths attributed to PCa [2] and [3].

Optimising therapy for elderly patients with metastatic castration-resistant PCa (mCRPC) remains challenging because they have greater comorbidities, physical frailty, and a lower tolerance for side effects [4], [5], [6], and [7]. These special medical considerations for elderly patients translate to a lower degree of participation in clinical trials [5], [6], and [8]. Elderly men diagnosed with PCa are often treated with localised therapy followed by androgen-deprivation therapy before developing mCRPC, which is initially treated with secondary hormonal therapies or chemotherapy [4], [5], [6], and [9]. Many elderly patients with mCRPC are frail and cannot tolerate chemotherapy-induced toxicities such as neutropenia, anaemia, and mucositis [4] . Consequently, elderly patients with mCRPC often do not receive chemotherapy and instead are only offered supportive care and monitored for disease progression [3] and [6]. Addressing the needs of elderly patients with metastatic disease therefore remains an important clinical goal.

Abiraterone acetate (AA) is a selective androgen biosynthesis inhibitor. In study COU-AA-301, AA plus prednisone (P) compared with placebo (PL) plus P improved overall survival (OS) in patients with mCRPC progressing after docetaxel, with favourable outcomes in the secondary end points of prostate-specific antigen (PSA) progression and radiographic progression-free survival (rPFS) [10] and [11]. Along with improvements in other indicators of clinical benefit, AA is now approved in >70 countries for treating the postdocetaxel patient population [12], [13], and [14]. We present the post hoc analyses of the efficacy and safety results for subgroups of elderly patients (aged ≥75 yr) and younger patients (aged <75 yr) with mCRPC progressing after docetaxel.

2. Patients and methods

2.1. Study design and patient population

Study COU-AA-301 (ClinicalTrials.gov identifier NCT00638690 ) was a phase 3 multinational, randomised double-blind PL-controlled study described previously [10] and [11]. Patients were stratified according to the Eastern Cooperative Oncology Group performance status (ECOG PS) grade, worst pain over previous 24 h, number of prior chemotherapies, and type of progression (radiographic vs biochemical). Eligible patients received a daily dose of 1000 mg AA plus 5 mg P twice daily or PL plus P. The primary end point was OS. Secondary end points included time to PSA progression (TTPP), rPFS, and PSA response rate ( Fig. 1 ).

gr1

Fig. 1 Study design. BID = twice daily; HR = hazard ratio; ITT = intention to treat; mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; PSA = prostate-specific antigen; rPFS = radiographic progression-free survival; TTPP = time to PSA progression. * Patients treated with previous ketoconazole or more than two prior chemotherapy regimens were excluded. OS was defined as time from randomisation to death from any cause; TTPP was defined as a 25% increase over the nadir PSA value, as defined by the PSA Working Group criteria [34] ; PSA response was defined as the proportion of patients achieving ≥50% decrease in PSA from pretreatment baseline PSA value confirmed after ≥4 wk; rPFS was determined based on imaging evaluation according to modified Response Evaluation Criteria in Solid Tumours or by bone scan; baseline lymph node size must be ≥2.0 cm to be considered a target lesion; progression on bone scans with two or more new lesions not consistent with tumour flare, confirmed on a second scan ≥6 wk later that shows one additional new lesion or more.

2.2. Key eligibility criteria

Eligible patients were aged ≥18 yr, with histologically or cytologically confirmed mCRPC, previously treated with docetaxel; had PSA progression according to the Prostate Cancer Working Group criteria or radiographic progression in soft tissue or bone with or without PSA progression; had prior orchiectomy or ongoing androgen deprivation with serum testosterone <50 ng/dl (<1.7 nM); had ECOG PS ≤2; and had haematology and chemistry laboratory values that met predefined criteria.

Patients were excluded due to serious or uncontrolled coexistent nonmalignant disease (including active and uncontrolled infection), abnormal liver transaminase test values (aspartate aminotransferase or alanine aminotransferase <2.5 times upper limit of normal), uncontrolled hypertension; active or symptomatic viral hepatitis or chronic liver disease, a history of pituitary or adrenal dysfunction, clinically significant heart disease, prior therapy with other investigational androgen receptor antagonist or cytochrome P450 c17 inhibitor, or prior therapy with ketoconazole.

2.3. Statistical analysis

For comparison between treatment groups, the Wilcoxon test was used for continuous laboratory parameters, and the chi-square test was used for all other categorical parameters including adverse event (AE) incidences. The stratified log-rank test was used to compare the treatment differences within each age subgroup. The Cox proportional hazards model was used to estimate the hazard ratio (HR) and its associated 95% confidence interval (CI). Distribution of time-to-event variables was estimated using the Kaplan-Meier product-limit method. The relative risk (RR; treatment vs control) is reported along with the associated 95% CI for dichotomous outcomes; statistical inference was evaluated using the chi-square test. Statistical significance was determined at the 0.05 level. No adjustment for multiplicity of testing was made for this post hoc analysis. The subgroup analyses for the primary end point were prespecified with a 75-yr age threshold and were used previously in age subgroup analyses [15] . Hence the threshold was chosen for the current analyses.

3. Results

3.1. Patient characteristics

In the AA plus P arm (n = 797) and in the PL plus P arm (n = 397), most patients were aged <75 yr (n = 863) compared with a combined total of 331 elderly patients (≥75 yr). Patient baseline characteristics in each age subgroup are shown in Table 1 and were balanced by treatment (p > 0.05). Among patients with recorded Gleason scores at initial diagnosis, 37% of elderly patients and 49% of patients <75 yr had scores ≥8. The proportion of patients with overall ECOG PS grade 2 was higher among elderly patients (15%) compared with younger patients (9%), and the median baseline PSA was higher in the PL plus P (180.7 ng/ml) versus the AA plus P (133.3 ng/ml) treated arm of elderly patients.

Table 1 Baseline disease characteristics

  Aged ≥75 yr * Aged <75 yr *
  AA plus P PL plus P AA plus P PL plus P
  n = 220 n = 111 n = 577 n = 286
Age, yr
n 220 111 577 286
 Median 78 78 66 66
 Range 75–95 75–90 42–74 39–74
Gleason score at initial diagnosis, n (%)
n 176 93 521 257
 ≤7 100 (57) 47 (51) 241 (46) 114 (44)
 ≥8 76 (43) 46 (49) 280 (54) 143 (56)
PSA at initial diagnosis, ng/ml
n 154 73 465 238
 Median 22.9 34 28 37.8
 Range 0.1–1900.0 1.1–4911.6 0.1–16065.9 1.5–7378.0
Extent of disease, n (%)
n 220 111 577 286
 Bone 195 (89) 102 (92) 515 (89) 256 (90)
 Node 98 (45) 49 (44) 263 (46) 115 (40)
 Liver 17 (8) 12 (11) 72 (13) 17 (6)
 Lungs 36 (16) 14 (13) 69 (12) 31 (11)
 Prostate mass 16 (7) 5 (5) 44 (8) 17 (6)
 Other tissue 9 (4) 6 (5) 30 (5) 12 (4)
ECOG PS, n (%)
n 220 111 577 286
 0 or 1 182 (83) 98 (88) 533 (92) 254 (89)
 2 38 (17) 13 (12) 44 (8) 32 (11)
Baseline PSA, ng/ml
n 216 108 572 285
 Median 133.3 180.7 127.1 127.6
 Range 1.6–6092 4.2–5438 0.4–9253 0.6–10114
Baseline haemoglobin, g/dl
n 214 108 565 281
 Median 11.7 11.7 11.8 11.9
 Range 8.4–15.0 8.0–14.8 7.3–16.1 7.2–16.5
Baseline lactate dehydrogenase (IU/l)
n 217 106 566 280
 Median 206 225 229 240
 Range 98–1864 124–2104 84–3373 123–5125

* For continuous laboratory parameters, the Wilcoxon test was used; for all other categorical parameters, the chi-square test was used; p > 0.05 for all baseline characteristics by treatment group.

AA = abiraterone acetate; ECOG PS = Eastern Cooperative Oncology Group performance status; P = prednisone; PL = placebo; PSA = prostate-specific antigen.

Among elderly patients, similar proportions treated with AA plus P versus PL plus P discontinued treatment due to disease progression (29% [63 of 218] vs 30% [33 of 109]) and due to AEs (15% [33 of 218] vs 18% [20 of 109]). Among younger patients receiving AA plus P versus PL plus P treatment, discontinuations due to disease progression were 37% (212 of 573) versus 32% (92 of 285), and discontinuations due to AEs were 13% (72 of 573) versus 18% (51 of 285) ( Fig. 2 ).

gr2

Fig. 2 Patient disposition. Safety population includes all patients who were randomised in the study and received study medication. AA = abiraterone acetate; P = prednisone; PL = placebo. * As of September 20, 2010.

3.2. Efficacy

The OS in elderly patients receiving AA plus P was significantly better than in those receiving PL plus P (HR: 0.64; 95% CI, 0.478–0.853; p = 0.0022; median: 15.6 vs 9.3 mo; Fig. 3 A). Younger patients receiving AA plus P treatment also had significant improvement in OS compared with patients taking PL plus P (HR 0.78; 95% CI, 0.652–0.930; p = 0.0055; median: 15.9 vs 12 mo; Fig. 3 A). Elderly patients in the AA plus P arm had a 34% reduction in TTPP relative to the PL plus P arm, although it was not statistically significant (HR: 0.76; 95% CI, 0.503–1.155; p = 0.1995; median: 11 vs 8.5 mo; Fig. 3 B). Younger patients treated with AA plus P had significant improvement in median TTPP versus those who received PL plus P (HR: 0.61; 95% CI, 0.474–0.779; p ≤ 0.0001; median: 8.4 vs 5.6 mo; Fig. 3 B). The elderly patient subgroup treated with AA plus P had a significantly longer time to rPFS compared with the PL plus P arm (HR: 0.66; 95% CI, 0.506–0.859; p = 0.0019; median: 6.6 vs 5.4 mo; Fig. 3 C). Similarly, the younger patients taking AA plus P also reported significantly longer rPFS (HR: 0.66; 95% CI, 0.564–0.776; p ≤ 0.0001; median 5.6 vs 3 mo; Fig. 3 C) compared with those who received PL plus P.

gr3

Fig. 3 Primary and secondary end points. (A) Overall survival by age group; (B) time to prostate-specific antigen (PSA) progression by age group; (C) radiographic progression-free survival by age group. CI = confidence interval; HR = hazard ratio.

For elderly patients, the PSA response rate was significantly higher with AA plus P (34%) versus PL plus P (8%) (RR: 4.15; 95% CI, 2.2–8.0; p ≤ 0.0001). The PSA response rate for patients <75 yr in the AA plus P arm compared with the PL plus P arm was 28% versus 5% (RR: 6.14; 95% CI, 3.6–10.6; p ≤ 0.0001). Hence AA plus P–treated patients in both age subgroups showed improved outcomes compared with PL in all end points, with the exception of TTPP in the elderly subgroup, where there was a trend towards an improvement.

3.3. Safety and tolerability

Both elderly and younger patients in the AA plus P arm had longer treatment duration than those in the PL plus P arm (35.6 vs 14.4 wk for elderly and 31.7 vs 15.7 wk for younger patients; Supplemental Table 1). Most patients in both age subgroups tolerated study treatment well, with ≤3% of patients having dose reductions across treatment arms. Three elderly patients and one younger patient taking AA plus P, compared with none in the PL plus P arm, had dose reductions due to AEs. Most patients did not report any dose interruptions, and in both age subgroups there was a consistent number of patients with more than one dose interruption across treatment arms (27% in the AA plus P arm vs 22% in the PL plus P arm for elderly patients and 18% vs 15%, respectively, for younger patients).

The most common AE for the AA plus P versus PL plus P treatment arms was fatigue in both elderly (48% vs 42%) and younger patients (47% vs 45%). Among AEs of special interest, which are related to the known effect of AA on mineralocorticoid excess, peripheral oedema, hypokalaemia, and hypertension were reported more frequently in the AA plus P–treated group compared with the PL plus P group. Elderly patients had a higher incidence of peripheral oedema (35%, AA plus P vs 28%, PL plus P; p = 0.3), although the difference between treatment arms was greater in younger patients (24% vs 15%; p < 0.01) ( Table 2 ). The incidence of hypokalaemia was higher in the AA plus P arm in both elderly and younger patients (18%, AA plus P vs 7%, PL plus P, and 18%, AA plus P vs 10%, PL plus P, respectively; p < 0.05). A slightly larger proportion of elderly patients taking AA plus P compared with PL plus P had AEs of atrial fibrillation and tachycardia (5% vs 1% and 5% vs 2%, respectively); the incidence in younger patients was consistent across treatment groups (2% vs 2% and 3% vs 2%), but none were statistically significant. When adjusting for the duration of exposure (event rate per 100 subject-years of exposure), treatment-emergent atrial fibrillation and tachycardia in elderly patients were higher in the AA plus P than in the PL plus P treatment group (8% vs 2% and 6% vs 3%, respectively). The rates were similar in the younger patient treatment groups (4% vs 4% and 5% vs 4%, respectively) (Supplemental Table 2). Overall, the treatment-emergent cardiac AEs leading to study discontinuation in the AA plus P group compared with the PL plus P group were similar in the elderly and the younger treated patients (1% vs 1%). Atrial fibrillation led to study treatment discontinuation of one elderly patient treated with PL plus P and one younger patient treated with AA plus P. Across the AA plus P and PL plus P treatment groups, the incidence of treatment-emergent cardiac events leading to death was low in both the elderly (2% vs 1%) and younger subgroups (1% each) (Supplemental Table 3).

Table 2 Adverse events (all grades [>15% in any subgroup] or grade 3 and 4) reported during treatment

  Aged ≥75 yr Aged <75 yr
  AA plus P

(n = 218)
PL plus P

(n = 109)
AA plus P

(n = 573)
PL plus P

(n = 285)
  All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
Subjects with treatment-emergent AE, n (%) 218 (100) 105 (48) 27 (12) 107 (98) 57 (52) 15 (14) 566 (99) 277 (48) 69 (12) 283 (99) 137 (48) 31 (11)
General AEs, n (%)
 Fatigue 104 (48) 27 (12) 1 (1) 46 (42) 11 (10) 1 (1) 268 (47) 43 (8) 1 (<1) 128 (45) 27 (10) 2 (1)
 Back pain 70 (32) 18 (8) 0 36 (33) 7 (6) 0 192 (34) 35 (6) 3 (1) 105 (37) 32 (11) 1 (<1)
 Arthralgia 62 (28) 8 (4) 0 26 (24) 3 (3) 0 177 (31) 32 (6) 0 69 (24) 14 (5) 0
 Constipation 60 (28) 3 (1) 0 32 (29) 1 (1) 0 163 (28) 7 (1) 0 94 (33) 3 (1) 0
 Anaemia 54 (25) 13 (6) 2 (1) 34 (31) 6 (6) 3 (3) 144 (25) 40 (7) 7 (1) 76 (27) 20 (7) 3 (1)
 Nausea 53 (24) 1 (1) 0 32 (29) 3 (3) 0 205 (36) 15 (3) 1 (<1) 98 (34) 8 (3) 0
 Vomiting 51 (23) 4 (2) 0 26 (24) 4 (4) 0 140 (24) 16 (3) 1 (<1) 75 (26) 8 (3) 0
 Bone pain 49 (23) 5 (2) 1 (1) 29 (27) 4 (4) 1 (1) 167 (29) 44 (8) 1 (<1) 88 (31) 22 (8) 3 (1)
 Asthenia 45 (21) 15 (7) 0 16 (15) 2 (2) 0 77 (13) 11 (2) 0 38 (13) 5 (2) 1 (<1)
 Diarrhoea 42 (19) 4 (2) 1 (1) 17 (16) 1 (1) 0 114 (20) 4 (1) 0 41 (14) 4 (1) 0
 Pain in extremity 37 (17) 3 (1) 0 22 (20) 7 (6) 0 119 (21) 20 (4) 1 (<1) 60 (21) 13 (5) 0
 Urinary tract infection 32 (15) 13 (6) 0 13 (12) 3 (3) 0 73 (13) * 9 (2) 0 16 (6) * 0 0
 Abdominal pain 30 (14) 4 (2) 0 16 (15) 2 (2) 0 72 (13) 14 (2) 0 31 (11) 6 (2) 0
AEs of special interest
 Peripheral oedema 77 (35) 3 (1) 0 31 (28) 0 0 135 (24) * 10 (2) 1 (<1) 44 (15) * 3 (1) 0
Cardiac disorders 43 (20) * 11 (5) 4 (2) 11 (10) * 1 (1) 1 (1) 63 (11) 14 (2) 5 (1) 22 (8) 3 (1) 2 (1)
 Atrial fibrillation 11 (5) 2 (1) 1 (1) 1 (1) 1 (1) 0 12 (2) 3 (1) 0 5 (2) 1 (<1) 1 (<1)
 Tachycardia 10 (5) 0 0 2 (2) 0 0 16 (3) 1 (<1) 0 6 (2) 0 0
Hypokalaemia 39 (18) * 10 (5) 1 (1) 8 (7) * 0 0 104 (18) * 21 (4) 3 (1) 28 (10) * 3 (1) 0
Hypertension 20 (9) 3 (1) 0 7 (6) 0 0 56 (10) 7 (1) 0 20 (7) 1 (<1) 0

* p < 0.05. A subject who had multiple events per system organ class or preferred term is counted twice, once in the column for the worst reported severity among the events and once in the All grades column. The All grades column includes all subjects with worst severities of an event that is less than grade 5, not simply subjects with grades 3 or 4.

AA = abiraterone acetate; AE = adverse event; P = prednisone; PL = placebo; PSA = prostate-specific antigen.

4. Discussion

Chemotherapy options for mCRPC patients have been studied extensively [16] and [17], although due to greater frailty and comorbidities, specific trials in elderly patients are lacking. In one retrospective study by Halabi et al., OS was assessed by age in patients with mCRPC with an ECOG PS score of 1 or 2 who may have been treated with docetaxel. In this study, the risk for death for patients aged 80–89 yr was higher than for patients 70–79 yr (HR: 1.3; p = 0.015) [18] . Hence less toxic therapy options with more manageable side effects that can be sustained for longer periods remain an important need for elderly men with mCRPC.

We evaluated whether the clinical benefit observed in the overall patient population with mCRPC after docetaxel was consistent within subgroups of elderly patients (aged ≥75 yr) and younger patients (aged <75 yr). The key limitation of the results is the post hoc nature of these analyses. Despite the limitation of post hoc analyses, we confirmed that the survival benefit observed in elderly patients (HR: 0.64; p = 0.0022) and younger patients (HR: 0.78; p = 0.0055) treated with AA plus P was consistent with that in the overall patient population (HR: 0.74; p < 0.0001) [10] and [11] when compared with PL plus P. The OS results are further supported by the secondary end points of the rPFS and PSA response rate, which were statistically significant in favour of the AA plus P arms across both age subgroups. An improvement in TTPP was also observed in the elderly subgroup, although this outcome did not reach statistical significance, as observed in the younger patients. A growing body of evidence indicates that stopping therapy in patients with apparent PSA progression alone is not appropriate. Consensus guidelines recommend against this practice because additional months or years of disease control can be realised, despite a slow rise in PSA [19] and [20].

The AE profiles for both age subgroups with respect to hypokalaemia, hypertension, and fluid retention were consistent and readily manageable, as described previously for the overall population [10] and [11]. The rates of cardiac disorders were slightly higher in the elderly population in the AA plus P arm compared with the PL plus P arm, whereas these AEs were similar across treatment groups in the younger patients. Elderly patients are particularly susceptible to cardiac toxicities, in part because of coexisting cardiac conditions. The observed cardiac AEs may be attributed to the known effect of AA on mineralocorticoid excess, which can result in fluid overload, hypokalaemia, and hypertension. These cardiac AEs were often readily managed in elderly patients by a timely diagnosis and the medical treatment of hypertension, hypokalaemia, and fluid retention—all modifiable risk factors for cardiac disorders. Notably, these cardiac AEs did not appear to increase the rate of treatment interruption or discontinuation or the incidence of AEs leading to death.

Although the current subgroup analyses examine the efficacy and safety in participating elderly patients, it is not clear if these elderly patients are representative of elderly patients in clinical practice or how the fitness of elderly patients relates to trial eligibility [4], [6], [8], and [21]. In this study, the selection criteria were applied to all patients regardless of age, and the treatment groups were balanced based on several baseline factors. Polypharmacy among elderly patients is common [4] . Studies addressing the drug–drug interactions with abiraterone can address this clinical concern [22] and [23]. In lieu of prospective clinical studies in elderly patients, these results provide much needed detailed safety and efficacy for elderly patients with mCRPC.

Docetaxel is an extensively studied first-line therapy for patients with mCRPC who have progressed after androgen-deprivation therapy [24], [25], [26], [27], and [28]. In the TAX 327 trial, a 3-wk regimen of docetaxel plus P showed an improvement of 2.9 mo in OS over mitoxantrone plus P in the overall study population [28] . In a subgroup analysis, for men aged ≥69 yr and ≤68 yr on the docetaxel plus P every-3-wk regimen, the HRs were quite similar: 0.81 and 0.77, respectively [28] . Docetaxel treatment is associated with increases in grade 3 or 4 neutropenia, diarrhoea, and neuropathy AEs [27] and [28]. Another retrospective study that assessed docetaxel-based chemotherapy in mCRPC patients aged ≥75 yr reported a median OS of 15 mo, with 46% of patients reporting grade 3 or 4 AEs and 40% reporting nonhaematologic grade 3 or 4 toxicities [15] . In TAX 327, in terms of AEs, elderly patients with a better ECOG PS score (≤1) appeared to have fared as well as younger patients [15] and [28].

Cabazitaxel improves survival in patients with mCRPC with progressive disease after docetaxel-based treatment compared with mitoxantrone and prednisone, but at the 25 mg/m2 dose of cabazitaxel used in the study, >80% of treated patients experienced severe haematologic toxicities (grade ≥3 neutropenia) [29] . Subgroup analyses in the same study showed that patients <65 yr had a better response than those ≥65 yr [29] . In the same study, a subgroup analysis by age may suggest greater incidence of neutropenia in patients ≥65 yr versus patients <65 yr (24% vs 18%), and of diarrhoea in patients ≥75 yr (56%) versus patients <75 yr (45%) [29] . Although the incidence of discontinuation due to AEs by age subgroups was not reported in this study, chemotherapy-based regimens are usually poorly tolerated by elderly patients [4] .

Enzalutamide, another hormonal agent that targets the androgen receptor signalling pathway, was recently shown to improve OS and was approved for patients with mCRPC after docetaxel [30] . A post hoc subgroup analysis of the AFFIRM study reported results that are consistent with those of the present study [31] . Despite the higher rate of some AEs (fatigue, diarrhoea, hot flushes, and peripheral oedema) in the elderly population treated with enzalutamide, the tolerability of enzalutamide versus PL appeared to be similar in younger and elderly patients [31] .

Radium-223, another approved agent for mCRPC after docetaxel, has also shown OS benefit, although the benefit for elderly patients has not been reported [32] .

Sipuleucel-T is approved for patients with asymptomatic/mildly symptomatic mCRPC in the United States based on a significant 4.1-mo benefit in OS compared with PL [33] . The median age was 71 yr, and approximately 16% of patients had received prior docetaxel [33] . A prespecified subgroup analysis of benefit based on age above or below the median and prior therapy with docetaxel or not did not show differences in HR for risk of death in either group [33] . Although sipuleucel-T was well tolerated, PSA decline or improvement in objective disease progression was not observed [33] .

5. Conclusions

This post hoc analysis of COU-AA-301 demonstrates that the risk–benefit ratio favours patients treated with AA in either age subgroup. Elderly patients derived clinical benefit similar to younger patients on AA plus P therapy compared with PL plus P. Although cardiac-related AEs were observed in a few subjects, they were slightly higher in elderly patients taking AA plus P; active monitoring and management of associated risk factors may mitigate the risk considerably. Elderly patients and younger patients experienced similar AEs, despite low-dose prednisone in both arms of the trial. This analysis is reassuring with respect to the risk–benefit ratio of treating elderly patients with AA, and AA is a viable treatment option for the elderly, either after docetaxel or for those not fit for docetaxel due to other comorbidities.

Presented at the 27th Annual European Association of Urology Congress, February 24–28, 2012, Paris, France.


Author contributions: Peter F.A. Mulders had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mulders, Molina, Kheoh, Haqq.

Acquisition of data: Mulders, Fizazi, Saad, Marberger, Higano, Chi.

Analysis and interpretation of data: Mulders, Molina, Li, Kheoh, Haqq.

Drafting of the manuscript: Mulders, Molina, Li, Kheoh, Haqq, Fizazi.

Critical revision of the manuscript for important intellectual content: Mulders, Molina, Marberger, Saad, Higano, Chi, Li, Kheoh, Haqq, Fizazi.

Statistical analysis: Kheoh, Li.

Obtaining funding: Molina, Haqq.

Administrative, technical, or material support: Molina, Haqq.

Supervision: Molina, Haqq.

Other (specify): None.

Financial disclosures: Peter F.A. Mulders certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Arturo Molina is an employee of Janssen Research & Development and holds stock in Johnson & Johnson. Fred Saad is a consultant and receives honoraria and research funding from Janssen and Astellas. Celestia S. Higano receives grants and is on the advisory board of Cougar Biotechnology; consults for Amgen, AstraZeneca, Bayer, Centocor OrthoBiotech, Dendreon, Genentech, GTx, Inc., Medivation, Millennium, Pfizer, BMS, Sanofi-Aventis, Teva Pharmaceuticals, Abbott Laboratories, Endo, Fresenius Kabi, Cougar Biotechnology, and Novartis; receives grants from Amgen, Aragon, BMS, Dendreon, Exelixis, ImClone, Medarex, Medivation, Millennium, OncoGenex, GlaxoSmithKline, Nerviano, Novartis, Cougar Biotechnology, Algeta, Genentech, and Teva; receives payment for development of educational presentations from Clinical Care Options, Medscape, Perceptive Informatics, Center for Biomedical Continuing Education, MD Anderson Cancer Center, Creative Educational Concepts, and Plexus Communications. Kim N. Chi is a consultant/adviser and receives honoraria and research funding from Janssen, Inc. Jinhui Li is an employee of Janssen Research & Development. Thian Kheoh is an employee of Janssen Research & Development and holds stock in Johnson & Johnson. Christopher M. Haqq is a former employee of Johnson & Johnson and holds stock in the company. Karim Fizazi participates on advisory boards and is a speaker for Amgen, Astellas-Medivation, Bayer, BMS, Dendreon, Exelixis, Ipsen, Janssen-Cougar, Keocyt, Millennium-Takeda, Novartis, Orion, and Sanofi-Aventis. Peter F.A. Mulders and Michael Marberger have nothing to disclose.

Funding/Support and role of the sponsor: All aspects of the study, including design and conduct, data collection, management, and analysis, were sponsored by Janssen Research & Development, Raritan, NJ, USA, and conducted on behalf of the Study 301 Investigators. Molina and Haqq provided administrative, technical, or material support and supervision on behalf of Janssen Research & Development (formerly Ortho Biotech Oncology Research & Development, unit of Cougar Biotechnology), Los Angeles, CA, USA. Writing assistance was funded by Janssen Global Services, LLC. The data interpretation and the preparation, review, and approval of the manuscript were a collaborative effort of all authors.

Acknowledgment statement: The authors acknowledge writing assistance provided by H. Koeller of PAREXEL.

Appendix A. Supplementary data

 

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Footnotes

a Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

b Janssen Research & Development, Los Angeles, CA, USA

c Medical University of Vienna, Vienna, Austria

d University of Montreal, Montreal, QC, Canada

e University of Washington, Seattle, WA, USA

f British Columbia Cancer Agency, Vancouver, BC, Canada

g Janssen Research & Development, Raritan, NJ, USA

h Institut Gustave Roussy, University of Paris Sud, Villejuif, France

lowast Corresponding author. Radboud University Nijmegen Medical Centre, Postbus 9101, 6500 HB Nijmegen, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands. Tel. +31 024 361 3735; Fax: +31 024 354 1031.